Certain oxime substituted pyrimidines are registered by the Chemical Abstracts Services (CAS) such as 4,6-diamino-5-pyrimidinecarboxaldehyde oxime (CAS Registry No.: 109831-69-8) and N,N′-dimethyl-5-[(methylimino)methyl]-4,6-pyrimidinediamine (CAS Registry No.: 14160-97-5) and described in Heterocycles, 1987, 25(1), 343-5. Certain references describe substituted pyrimidine compounds such as United States patents: U.S. Pat. Nos. 6,080,750, 6,107,301 and 6,833,378.
The preparation of various 2,4,6-substituted pyrimidines is described in O'Brien D E, Baiocchi F, Robins R and Cheng C C, Pyrimidines. VII. 2-Amino-4-(Substituted Anilino)Pyrimidines, Journal of Organic Chemistry, 1962, 27, 1104-7.
The solid phase synthesis of various diamino-substituted pyrimidines is described in Barillari C., Barlocco D. and Raveglia L. F., Solid Phase Synthesis of Diamino-Substituted Pyrimidines, European Journal of Organic Chemistry, 2001, (24), 4737-4741.
The condensation of a 2,6-diamino-4-chloro-pyrimidine with an aminoazobenzene and subsequent coupling of the product with diazotized arylamines is described in Abdel-Razik H. H., Refat H. M. and Zaki, M. E. A., Synthesis of Some New 2,6-Diamino-4-(p-Arylazo)Anilinopyrimidine and Some Related 5-Arylazopyrimidine Derivatives for Dyeing Synthetic Fabrics, Heterocyclic Communications, 2001, 7 (3), 263-270.
Nucleophilic aromatic substitution has been used as a general approach for the synthesis of pyrimidine derivatives from halopyrimidines (as described in Gomtsyan A, Didomenico S, Lee C-Hung, Matulenko M A, Kim K, Kowaluk E A, Wismer C T, Mikusa J, Yu H, Kohlhaas K, Jarvis M F, Bhagwat S S, Design, Synthesis, and Structure-Activity Relationship of 6-Alkynylpyrimidines as Potent Adenosine Kinase Inhibitors, J. Med. Chem. 2002, 45 (17), 3639-3648; Chapman N B, Rees C W, Nucleophilic displacement reactions in aromatic systems. III. Kinetics of the reactions of chloronitropyridines and chloropyrimidines with piperidine, morpholine, pyridine, and aniline, J. Chem. Soc. 1954, 1190-6; Hartung C H, Backes A C, Beatrice F, Missio A, Philipp A, Efficient microwave-assisted synthesis of highly functionalized pyrimidine derivatives, Tetrahedron, 2006, 62, 10055-10064; and Maggiolo A, Phillips A P, Hitchings G H, Synthesis of 2-methyl-4-amino-6-(substituted-amino) pyrimidines, J. Am. Chem. Soc., 1951, 73, 106-7).
The hydrolysis of chloropyrimidines to hydroxyl pyrimidines in strong hydrochloric acid solutions at elevated temperature has also been described (see Maggiolo A and Phillips A P, J. Org. Chem. 1951, 16. 376-382).
Accordingly, there remains a need for a process to selectively displace a halogen atom on an aldehyde-substituted pyrimidine with an amine nucleophile.